Dementia is a common, debilitating feature that develops in 40-70% of patients with Parkinson's disease (PD) with an incidence approximately six times higher in PD patients than age-matched controls. Several independent neuropathologists have indicated that approximately 50% of patients with PD-dementia (PDD) will have changes in brain that meet pathological criteria for a diagnosis of both Alzheimer's disease (AD) and PD. Such findings indicate that mixed pathology is surprisingly common and that shared pathways likely contribute to abnormal deposition of tau and 1-synuclein. The mechanisms underlying the development of mixed pathology, however, are enigmatic, and no clear-cut model for their evaluation currently exists. Several exciting new observations indicate that our line of DJ-1-deficient mouse (i.e. DJ-1 deletion Exon 7 (DJ-1-/-)) may provide, for the first time, a model to address these mechanisms. We now have preliminary data in aged DJ-1-/- mice demonstrating robust phosphorylated tau and ?-synuclein accumulation throughout the brain, in what may represent early neurodegenerative mixed pathology. Our initial analyses show that these changes are accompanied by i) neuronal cell loss in the substantia nigra, ii) evidence of oxidative damage and iii) chaperone depletion, suggesting that the absence of DJ-1 function could contribute to neurodegeneration and the development of ? -synuclein and tau inclusions. Thus, the DJ-1-/- mouse could be used as a novel and important tool to investigate pathways leading to cell death and mixed pathology in disorders with parkinsonism and dementia. The purpose of this proposal is to take advantage of our null DJ-1 model and to explore, for the first time, the relationship between ?-synuclein, tau and DJ-1, and the potential role of these interactions, in the pathophysiology underlying mixed tau and ?-synucleinopathies. PUBLIC HEALTH RELEVANCE: The long-term goal of this research is to elucidate novel targets for treating or preventing cognitive decline in Parkinson's disease (PD), a major and untreatable cause of disability in the disorder, and an essential starting point is to better understand the pathological substrates of dementia in PD and the underlying mechanisms that contribute to disease development. Our neuropathological evidence suggests, that for the first time, we have a rodent model to evaluate these pathways and gain novel insight into the protein-protein interactions that lead to degeneration and mixed ? -synuclein and tau pathology. The studies proposed in this application should be useful in determining precise mechanisms that contribute to tau and ?-synuclein pathogenesis (e.g., oxidative stress from DJ-1 deficiency and/or toxicant exposure), the relationship of these proteins with DJ-1 and the impact of gene-environment and gene-gene interactions in pathophysiology leading to parkinsonism with dementia.